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Selective reduction of blood flow to white matter during hypotension in newborn dogs: a possible mechanism of periventricular leukomalacia.

The cerebrovascular response of newborn animals to hypotension has not been defined on a regional basis. Using an autoradiographic technique employing 14C-iodoantipyrine as indicator, we studied the cerebral physiological responses of newborn dogs to hypotension induced by exsanguination or by administration of Escherichia coli endotoxin. Regional cerebral blood flow (rCBF) to all gray matter structures was preserved, even at mean arterial pressures as low as 20 mm Hg. In contrast, rCBF to periventricular and occipital white matter decreased significantly during severe hypotension. The selective hypoperfusion of cerebral white matter during severe hypotension may provide a mechanistic explanation for the pathogenesis of periventricular leukomalacia.

Animals↗

Anoxic injury of mammalian central white matter: decreased susceptibility in myelin-deficient optic nerve.

The rat optic nerve, a typical central nervous system white matter tract, rapidly loses excitability when it is exposed to anoxia and is irreversibly damaged by prolonged anoxia. Neonatal optic nerve is extremely resistant to anoxia-induced dysfunction and injury; the adult pattern of response to anoxia appears between 10 and 20 days postnatal, that is, during the period of oligodendroglial proliferation and myelination. To test the hypothesis that myelination, or associated events, confer anoxic susceptibility on developing white matter, we analyzed the effects of anoxia on the myelin-deficient (md) strain of rat. Acutely isolated optic nerves from 19- to 21-day-old md rats and control optic nerves from unaffected male littermates were maintained in vitro at 37 degrees C, and exposed to a standard 60-minute period of anoxia. The supramaximal compound action potential was recorded and amplitude of the compound action potential, expressed as % of amplitude before anoxic exposure, was determined. The compound action potential was nearly abolished within 3 to 6 minutes after onset of anoxia in control optic nerves, while optic nerves from md rats displayed a slower decrease in compound action potential amplitude during anoxia, with a distinct action potential present even after 60 minutes of anoxia. Optic nerves from md rats showed significantly greater recovery of compound action potential (71 +/- 25%) than did control optic nerves (33 +/- 21%; p less than 0.02) after 60 minutes of anoxia. These findings support the hypothesis that myelination, or changes associated with it, may be important in the development of anoxic susceptibility in central white matter.

Action Potentials↗

Na(+)-Ca2+ exchanger mediates Ca2+ influx during anoxia in mammalian central nervous system white matter.

White matter of the mammalian central nervous system suffers irreversible injury after prolonged anoxia, which can result in severe neurological impairment. This type of injury is critically dependent on Ca2+ influx into cells. We present evidence that the Na+,Ca2+ exchanger mediates the majority of the damaging Ca2+ influx into cells during anoxia in white matter. Anoxic injury was studied in the isolated rat optic nerve, and functional recovery was monitored using the compound action potential. Blockers of voltage-gated Na+ channels (tetrodotoxin and saxitoxin) significantly improved recovery, as did perfusion with zero-Na+ solution; both maneuvers would prevent intracellular [Na+] from rising and thus prevent Ca2+ influx by inhibiting reverse operation of the Na+,Ca2+ exchanger. Direct pharmacological blockade of the Na+,Ca2+ exchanger during anoxia with bepridil or benzamil also significantly improved recovery. These findings suggest that reverse operation of the Na+,Ca2+ exchanger during anoxia is a critical mechanism of Ca2+ influx and subsequent white matter injury.

Amiloride↗

Visual attentional disturbance with unilateral lesions in the basal ganglia and deep white matter.

To elucidate the role of the basal ganglia and deep white matter in the visual attention mechanism, a new visual attention task was carried out by 15 patients, 9 with left-side and 6 with right-side basal ganglia and/or deep white matter damage without visual field defects, and by 12 normal subjects. Their reaction times were recorded in response to a random visual stimulation by pushing a button with the hand ipsilateral to the side of the lesion. All the patients with damage to the right side of the brain had a longer reaction time in the left space than in the right or middle space. With conventional test, only one of them showed left unilateral spatial neglect. Seven of the 9 patients with a left lesion had a significantly longer reaction time in the right space than in the left. None had unilateral spatial neglect. Both the right and left brain-damaged groups showed longer reaction times in both spaces, compared to the normal groups. There was no significant difference in reaction time among the control subjects. These findings suggest that the basal ganglia and deep white matter in each hemisphere play some role in directing visual attentional factors into both spaces. Visual attentional disturbance was highly evident even with left-side brain damage, and this kind of disturbance is not usually revealed with the current tasks used for testing unilateral spatial neglect.

Adult↗

Morphometry of in vivo human white matter association pathways with diffusion-weighted magnetic resonance imaging.

The precise characterization of cortical connectivity is important for the understanding of brain morphological and functional organization. Such connectivity is conveyed by specific pathways or tracts in the white matter. Diffusion-weighted magnetic resonance imaging detects the diffusivity of water molecules in three dimensions. Diffusivity is anisotropic in oriented tissues such as fiber tracts. In the present study, we used this method to map (in terms of orientation, location, and size) the "stem" (compact portion) of the principal association, projection, and commissural white matter pathways of the human brain in vivo, in 3 normal subjects. In addition, its use in clinical neurology is illustrated in a patient with left inferior parietal lobule embolic infarction in whom a significant reduction in relative size of the stem of the left superior longitudinal fasciculus was observed. This represents an important method for the characterization of major association pathways in the living human that are not discernible by conventional magnetic resonance imaging. In the clinical domain, this method will have a potential impact on the understanding of the diseases that involve white matter such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, head injury, and spinal cord injury.

Cerebral Cortex↗

Developmental regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. II. Human cerebral white matter and cortex.

This report is the second of a two-part evaluation of developmental differences in alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit expression in cell populations within white matter and cortex. In part I, we reported that, in rat, developmental expression of Ca2+-permeable (GluR2-lacking) AMPARs correlated at the regional and cellular level with increased susceptibility to hypoxia/ischemia (H/I), suggesting an age-specific role of these receptors in the pathogenesis of brain injury. Part II examines the regional and cellular progression of AMPAR subunits in human white matter and cortex from midgestation through early childhood. Similarly to the case in the rodent, there is a direct correlation between selective vulnerability to H/I and expression of GluR2-lacking AMPARs in human brain. For midgestational cases aged 20-24 postconceptional weeks (PCW) and for premature infants (25-37 PCW), we found that radial glia, premyelinating oligodendrocytes, and subplate neurons transiently expressed GluR2-lacking AMPARs. Notably, prematurity represents a developmental window of selective vulnerability for white matter injury, such as periventricular leukomalacia (PVL). During term (38-42 PCW) and postterm neonatal (43-46 PCW) periods, age windows characterized by increased susceptibility to cortical injury and seizures, GluR2 expression was low in the neocortex, specifically on cortical pyramidal and nonpyramidal neurons. This study indicates that Ca2+-permeable AMPAR blockade may represent an age-specific therapeutic strategy for potential use in humans. Furthermore, these data help to validate specific rodent maturational stages as appropriate models for evaluation of H/I pathophysiology.

Adult↗

Electron-microscopic identification of Marchi-positive bodies and argyrophilic granules in the spinal cord white matter of the guinea pig.

Sections from spinal cord white matter of normal and rhizotomized guinea pigs fixed by glutaraldehyde perfusion were stained with Marchi fluid or according to a suppressive silver technique. With the aid of the section-embedding method thin sections, cut from light-microscopically identified areas containing Marchi-positive bodies or argyrophilic granules, were examined in the electron microscope. The results show that the Marchi-positive bodies and argyrophilic granules, which are present in normal white matter, represent different histochemical expressions of the same entity--the myelinoid body. In view of the similarities between myelinoid bodies and myelin fragments formed during Wallerian degeneration it is suggested that this type of so called artifact staining of normal white matter inherent to both methods should instead be considered as an expression of a specificity of the two methods for degenerating nervous elements.

Animals↗

Subcortical white matter lesions and functional impairment in geriatric depression.

Geriatric depression is associated with significant functional impairment. There is also growing evidence linking vascular brain changes to depression in late life. We sought to examine the relationship between cerebrovascular disease and impairment in basic activities of daily living (BADL) and instrumental activities of daily living (IADL) in a group of older depressives. The sample consisted of 224 depressed adults aged 60 years and above enrolled in Duke's Mental Health Clinical Research Center. All subjects had unipolar major depression and were free of other major psychiatric and neurological illness, including dementia. In a structured interview, subjects reported their medical history and ability to perform both BADL and IADL. Geriatric psychiatrists assessed cognition using the Mini Mental State Examination (MMSE) and depression severity using the Montgomery Asberg Depression Rating Scale (MADRS). Subjects had a standardized magnetic resonance imaging (MRI) brain scan. MRI scans were processed using a semi-automated method to determine volumes of subcortical white matter lesions (WML) and subcortical gray matter lesions (GML). Logistic regression was used to examine effects of WML and GML controlling for demographic and clinical factors. Greater volume of WML was associated with impairment in both BADL and IADL, while GML was associated with IADL impairment. In logistic models, WML remained significantly associated with IADL after controlling for the effects of age, gender, depression severity, and medical comorbidity. We concluded that white matter lesions are independently associated with functional impairment. Further studies are needed to understand how these lesions affect function, e.g., through effects on cognition or motor skills.

Activities of Daily Living↗

[Dry matter losses in mushroom (Lactarius rufus) by blanching].

According to recommended international standards edible fungi are blanched before salting and freezing. A study was conducted on the solution losses of Lactarius rufus due to blanching. Weight losses, changes of dry matter, raw fat, total nitrogen, amino nitrogen and ash contents as well as the pH value were determined when various methods of blanching were used. 3 min blanching at 95-100 degrees C was able to inactivate catalase and peroxydase while 6 min blanching was needed for inactivating polyphenoloxydase totally. After blanching there were 1/10 - 1/100 of spores left. During the 3 min blanching in water five times the quantity of mushrooms the losses of dry matter were about 10%; when doubling the quantity of blanching water the losses increased to 2-3 fold. The doubling of blanching time had no significant influence on the losses. The soluble dry matter content of blanched mushrooms was less than 50% of that of the fresh. Total nitrogen of fresh mushrooms was equal to that of the blanched but the amino nitrogen decreased to one tenth by blanching. The mineral element content of blanched mushrooms was about the half of that of the fresh. Blanching caused a slight decrease in the pH value. The necessity of the blanching of all edible fungi before freezing was discussed.

Basidiomycota↗

Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis.

Transplanted neural precursor cells remyelinate efficiently acutely demyelinated focal lesions. However, the clinical value of cell transplantation in a chronic, multifocal disease like multiple sclerosis will depend on the ability of transplanted cells to migrate to the multiple disease foci in the brain. Here, we expanded newborn rat neural precursor cells in spheres and transplanted them intracerebroventricularly or intrathecally in rats. The cells were labeled by the nuclear fluorescent dye Hoechst or by incubation with BrdU to enable their identification at 2 days and 2 weeks after transplantation, respectively. Spheres consisted of PSA-NCAM(+), nestin(+), NG2(-) undifferentiated precursor cells that differentiated in vitro into astrocytes, oligodendrocytes, and neurons. Spheres that were transplanted into intact rats remained mostly in the ventricles or in the spinal subarachnoid space. Following transplantation at peak of experimental autoimmune encephalomyelitis, cells migrated into the brain or spinal cord parenchyma, exclusively into inflamed white matter but not into adjacent gray matter regions. After 2 weeks, many transplanted cells had migrated into distant white matter tracts and acquired specific markers of the astroglial and oligodendroglial lineages. Thus, the inflammatory process may attract targeted migration of transplanted precursor cells into the brain parenchyma.

Acute Disease↗

Transplantation of glial-restricted precursor cells into the adult spinal cord: survival, glial-specific differentiation, and preferential migration in white matter.

Glial-restricted precursor (GRP) cells are among a number of candidate cells for transplantation repair of CNS injury. The isolation and characterization of these cells in vitro have been described previously, but their in vivo properties are not well understood. We examined the fate and migration of grafted fetal GRP cells harvested from alkaline phosphatase-expressing transgenic rats into intact and injured spinal cord. Transplanted GRP cells survived for at least 6 weeks and differentiated along astrocytic and oligodendrocytic but not neuronal lineages. Cells grafted into the intact spinal cord exhibited robust migration along longitudinal white matter tracts and by 6 weeks migrated more than 15 mm. In contrast, migration of GRP cells in the gray matter was very limited. We then examined the phenotypic properties of proliferating endogenous precursors in response to injury by BrdU labeling. The predominant proliferating population seen after injury consisted of GRP-like cells with Nkx2.2/olig2 phenotype. Incorporation of BrdU by endogenous cells suggests that the environment provides proliferation signals and is permissive to glial precursor survival. To test if exogenous GRP cells would respond similarly, we transplanted GRP cells into a lateral funiculus injury. GRP cells survived and differentiated along glial lineages and migrated along white matter tracts in the injured spinal cord. Directed homing toward the lesion was not seen and there was no significant bias in differentiation between cells transplanted into injured and uninjured spinal cord. GRP cell transplants may therefore provide a cellular transplant that can respond to appropriate endogenous cues to produce therapeutic molecules and new glial cells after injury.

Animals↗

Developmental apoptosis in the spinal cord white matter in neonatal rats.

We investigated developmental apoptosis in the white matter of the cervical spinal cord at postnatal days 2, 5, and 8. Apoptotic cells were labeled using TUNEL and caspase-3 immunostaining. Apoptotic cells were diffusely distributed throughout the white matter of the spinal cord. The total amount of apoptotic cells in the cervical spinal cord white matter was related to postnatal age, with the lowest at P2 (mean 7.9, SD 5.6) and the highest at P8 (mean 109, SD 21.4). Using double immunostaining for ED-1 and O4, apoptotic cells were identified as microglia and oligodendrocytes.

Aging↗

Relationship between periventricular and deep white matter lesions and depressive symptoms in older people. The LADIS Study.

BACKGROUND: Both types of cerebral white matter hyperintensities, periventricular (PVL) and deep white matter lesions (DWML) have been previously associated with the development of depression in older subjects. However, it remains controversial as to whether PVL, DWML, or both are most strongly associated with depression and this was the aim of the current study. METHODS: In a pan-European multicentre study of 626 older subjects, we examined the relationship between PVL and DWML, depressive symptoms (GDS quintile), cognitive status (MMSE), hypertension and history of stroke. RESULTS: In univariate analysis we found that depressive symptoms as assessed by GDS were associated with both types of white matter lesions (Spearman rho = 0.12 p = 0.002 for DWML and rho = 0.09 p = 0.01 for PVL). Using ordinal logistic regression analysis the total DWML score (p = 0.041), rather than PVL (p = 0.9) was found to predict GDS scores. CONCLUSIONS: DWML, but not PVL, were most strongly associated with depressive symptoms in this sample. As DWML (unlike PVL) are associated with vascular ischaemic damage, our findings are consistent with the 'vascular depression' hypothesis. Longitudinal studies are needed to clarify the time course of these relationships, in particular, whether modifying DWML alters the natural history of depression.

Age of Onset↗

The relation of White Matter Hyperintensities to implicit learning in healthy older adults.

OBJECTIVE: This study examined whether MRI evidence of cerebrovascular disease in the form of white matter hyperintensities (WMH) was associated with decreased implicit sequence learning performance in a high-functioning group of normal elderly volunteers. METHOD: One hundred and eight community-dwelling elderly individuals received an MRI and performed an implicit sequence learning task, the serial reaction time (SRT) task. RESULTS: Hyperintensities present in the white matter were associated with a decreased learning effect. This association was found with both deep white matter and periventricular changes. Other factors affecting SRT performance (i.e., baseline reaction time and switch-cost) were not significantly related to the presence of WMH. CONCLUSIONS: The results indicate that in addition to previously identified generalized cognitive deficits, WMH are also associated with a specific decrease in the implicit learning of sequences.

Aged↗

White matter tractography using diffusion tensor deflection.

Diffusion tensor MRI provides unique directional diffusion information that can be used to estimate the patterns of white matter connectivity in the human brain. In this study, the behavior of an algorithm for white matter tractography is examined. The algorithm, called TEND, uses the entire diffusion tensor to deflect the estimated fiber trajectory. Simulations and imaging experiments on in vivo human brains were performed to investigate the behavior of the tractography algorithm. The simulations show that the deflection term is less sensitive than the major eigenvector to image noise. In the human brain imaging experiments, estimated tracts were generated in corpus callosum, corticospinal tract, internal capsule, corona radiata, superior longitudinal fasciculus, inferior longitudinal fasciculus, fronto-occipital fasciculus, and uncinate fasciculus. This approach is promising for mapping the organizational patterns of white matter in the human brain as well as mapping the relationship between major fiber trajectories and the location and extent of brain lesions.

Algorithms↗

Cognitive functions correlate with white matter architecture in a normal pediatric population: a diffusion tensor MRI study.

A possible relationship between cognitive abilities and white matter structure as assessed by magnetic resonance diffusion tensor imaging (DTI) was investigated in the pediatric population. DTI was performed on 47 normal children ages 5-18. Using a voxelwise analysis technique, the fractional anisotropy (FA) and mean diffusivity (MD) were tested for significant correlations with Wechsler full-scale IQ scores, with subject age and gender used as covariates. Regions displaying significant positive correlations of IQ scores with FA were found bilaterally in white matter association areas, including frontal and occipito-parietal areas. No regions were found exhibiting correlations of IQ with MD except for one frontal area significantly overlapping a region containing a significant correlation with FA. The positive direction of the correlation with FA is the same as that found previously with age, and indicates a positive relationship between fiber organization and/or density with cognitive function. The results are consistent with the hypothesis that regionally specific increased fiber organization is a mechanism responsible for the normal development of white matter tracts.

Adolescent↗

ATPase activities in myelin and oligodendrocytes isolated from the brains of developing rats and from bovine brain white matter.

Of the Na,K-ATPase activity in brain homogenates from 20-, 60-, and 120-day-old rats, 1.4 to 2.6% was recovered in myelin. The relative specific activities, at 0.2 to 0.3 times the specific activities in the rat brain homogenates, did not decrease during development, and myelin from bovine brain white matter had a similar relative specific activity. Oligodendrocytes from rat brains and bovine white matter had approximately one third the Na,K-ATPase specific activities found in myelin from the respective sources. The Mg-ATPase activity in rat brain myelin decreased during development and, in myelin from adult rats, was much lower than the Na,K-ATPase activity. Notably, oligodendrocytes from both the forebrains of 10- to 120-day-old rats and from bovine white matter had high Mg-ATPase activities. Whereas Na,K-ATPase may be intrinsic to certain regions of the myelin sheath, the Mg-ATPase in isolated myelin probably arises from fragments of oligodendrocyte membranes.

Adenosine Triphosphatases↗

Extracellular matrix of central nervous system white matter: demonstration of an hyaluronate-protein complex.

Monoclonal antibodies were raised against human glial hyaluronate-binding protein (GHAP), a major CNS-specific glycoprotein known to bind hyaluronate in vitro. Frozen sections of dog and human spinal cord were digested with Streptomyces hyaluronidase in order to ascertain whether GHAP is bound to hyaluronate in vivo. Digestion with hyaluronidase, prior to staining of the sections by conventional indirect immunofluorescence, led to a drastic reduction in the intensity of the staining reaction. Chondroitinase ABC (protease-free) was also effective in bringing about the release of GHAP from tissue sections. This enzyme also degrades hyaluronate. The effects of the chondroitinase were completely reversed by the addition of 1 mM Zn2+, a known inhibitor of this enzyme. The intact protein was released into the soluble fraction of human brain homogenates by testicular hyaluronidase. An immunoreactive species of 70 kD was released into the soluble fraction of dog spinal cord homogenates by Streptomyces hyaluronidase. Dog GHAP was isolated from spinal cord by means of ion exchange and affinity chromatography. This protein bound efficiently to hyaluronate in vitro. Dog and human GHAP had identical isoelectric points and similar peptide maps but different molecular weights. Dog GHAP (70 kD) was larger than its human counterpart (60 kD). These findings imply that GHAP exists in association with hyaluronate in CNS white matter. Immunoelectron microscopy revealed that GHAP fills the space between myelin sheaths in dog spinal cord white matter. One is led to conclude therefore that an hyaluronate based extracellular matrix exists in CNS white matter.

Amidohydrolases↗